Tuberculosis (TB) has attracted attention as a leading global public problem resulting in the commitment of substantial resources to research and control activities. Although significant scientific advances have ensued, key translational tools are lacking. Chief among these are biomarkers to assist in developing new approaches and modalities for the prevention and management of TB. Their development has been retarded, in part, is because of limited understanding of the host-bacterial relationship. The current proposal broadens the focus of the U.S.-Brazil collaboration to address more fundamental issues concerning host susceptibility to Mycobacterium tuberculosis (Mtb) infection, the immunodynamics of recent TB infection, and bacterial factors that may play a role in treatment relapse. The high impact translational goal of this program, then, is to discover biomarkers of clinical importance to the prevention and treatment of TB. The Specific Aims are 1 .To determine the immunologic basis for resistance and susceptibility to Mtb infection and the correlate biomarkers. The results may provide new concepts as well as biomarkers relevant to the development of novel treatments, TB vaccines and adjuvants that target innate immunity. 2. to elucidate the immunodynamics of evolving Mtb infection and to discover measurable biomarkers in clinical samples that could accurately identify recent Mtb infection and/or active Mtb replication, thereby identifying persons at high risk of TB. 3. to determine whether Mtb isolates associated with relapse 1) have sub clinical resistance below or around clinical breakpoints for the antibiotic, 2) are more tolerant of antibiotics as measured by BACTEC assays or 3) display a loss-of-synergy phenotype. Further, to determine whether genetic mechanisms associated with these phenotypes include 1) embB mutations, 2) pump mutations such as iniA 3) and to discover other as yet unknown mechanisms. These studies will characterize phenotypic and genotypic biomarkers of Mtb that are associated with treatment failure. TB patients infected with such isolates may require alternative approaches to treatment. RELEVANCE (See instructions): TB is a major global public health concern. The available approaches to prevention and control of TB have failed. This research will provide biomarkers that will be essential to develop improved tools and approaches to control TB.